title: Methylene blue rescues heart defects in a Drosophila model of Friedreich's ataxia.
abstract: Friedreich's ataxia (FRDA), the most common hereditary ataxia, is characterized by progressive degeneration of the central and peripheral nervous system, hypertrophic cardiomyopathy and a high risk of diabetes. FRDA is caused by abnormally low levels of frataxin, a highly conserved mitochondrial protein. Drosophila has been previously successfully used to model FRDA in various cell types, including neurons and glial cells. Here, we report the development of a Drosophila cardiac model of FRDA. In vivo heart imaging revealed profound impairments in heart function in frataxin-depleted Drosophila, including a strong increase in end-systolic and end-diastolic diameters and a decrease in fractional shortening (FS). These features, reminiscent of pathological phenotypes in humans, are fully rescued by complementation with human frataxin, suggesting conserved cardiac functions of frataxin between the two organisms. Oxidative stress is not a major factor of heart impairment in frataxin-depleted flies, suggesting the involvement of other pathological mechanisms notably mitochondrial respiratory chain (MRC) dysfunction. Accordingly, we report that methylene blue (MB), a compound known to act as an alternative electron carrier that bypasses mitochondrial complexes I-III, was able to prevent heart dysfunction. MB also partially rescued the phenotype when administered post-symptomatically. Analysis of MB derivatives demonstrates that only compounds with electron carrier properties are able to prevent the heart phenotype. Thus MB, a compound already used for several clinical applications, appears promising for the treatment of the heart dysfunctions that are a major cause of death of FRDA patients. This work provides the grounds for further evaluation of MB action in mammals.
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA) EAC4413 CNRS, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Tricoire
authors.forename: Amandine
authors.initials: A
authors.lastname: Palandri
authors.forename: Arthur
authors.initials: A
authors.lastname: Bourdais
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Camadro
authors.forename: Véronique
authors.initials: V
authors.lastname: Monnier
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D004353:Drug Evaluation, Preclinical; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology* / Q000627:therapeutic use; D034622:RNA Interference; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology; D000096923:Frataxin
chemical_list: D002316:Cardiotonic Agents; D029721:Drosophila Proteins; D033862:Iron-Binding Proteins; D008751:Methylene Blue; D014451:Ubiquinone; D000096923:Frataxin; C036619:idebenone